Development of lesions in inflammatory demyelinating diseases, such as multiple sclerosis (MS) and Guillain-Barre syndrome (GBS), is associated with perivascular inflammation, invasion of the nervous tissue by cells of the immune system, and specific attack on the myelin sheath. It is not clear what the initial lesion is, how cells are attracted to the myelin, or how they cross the blood- brain barrier (in MS) or blood-nerve barrier in GBS)- Mast cells are situated in strategic perivascular locations in both the peripheral (PNS) and central (CNS) nervous systems. Although the numbers of mast cells in the nervous system are low, especially in the CNS, the explosive nature of their degranulation, leading to secretion of vasoactive amines, chemoattractants, and proteases, suggests the possibility of their involvement in the early stages of a demyelinating lesion. This project is designed to examine the extent of this involvement by use of in vitro and in vivo techniques. The interaction of isolated mast cells with myelin components and with cultured glial cells will be examined to study the effects of mast cell degranulation on the myelin sheath and glial cells, and to see whether substances present in the area of a demyelinating lesion stimulate degranulation of mast cells. The potential of glial cells to support mast cell growth and the effect of maturation in a nervous system environment will be examined by coculture with different mast cell populations. In vivo studies will examine tissues from experimentally demyelinating animals for pathological evidence of a role for mast cells in demyelination, and sera will be assayed for evidence of mast cell involvement, such as increases in histamine or IgE. Various manipulations of mast cells, including use of drugs to block mast cell degranulation, compounds that specifically degranulate mast cells, and mutant mice lacking mast cells will be employed to further define the extent of mast cell involvement.